Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor

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• 作者：Nicholas D. Measom ; Kenneth D. Down ; David J. HirstCraig Jamieson ; Eric S. Manas ; Vipulkumar K. Patel ; Don O. Somers
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：43-48
• 全文大小：402K
• ISSN：1948-5875

文摘

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA₂ inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.